Inflammaging and Diabetic Retinopathy

PROJECT SUMMARY Diabetic retinopathy (DR) is a neurovascular complication of diabetes mellitus and the leading cause of blindness in adults. Prevention of hyperglycemia-induced retinal microvascular dysfunction remains one of the therapeutic goal to preserve vision in diabetic patients. Recent insights from our group and others have shown that hyperglycemia results in retinal endothelial cells (RECs) stress-induced premature senescence (SIPS), a senomorphic process characterized by the acquisition of the so-called senescence-associated secretory phenotype (SASP) and linked to chronic inflammation. The exact causes and consequences of this mechanism and its relative impact in DR are presently unknown and understudied. Evidence provided by the literature and our own preliminary results suggests that central to the development of SIPS is the increased expression and activity of the histone deacetylase 6 (HDAC6) paralleled by loss of the NAD+-dependent histone deacetylase SIRT-1. This imbalance results in a switch in cell acetylome that has proven to result in mitochondrial dysfunction and has been linked to the pathogenesis of a number of pathologies including diabetic complications and neurodegeneration. In addition, we have found that exosomes isolated from diabetic RECs could propagate senomorphic and pro-inflammatory signals to neighboring vascular cells and to recruited neutrophils to promote degenerative changes such as netosis. Our overall working hypothesis is that altered SIRT-1-HDAC6 balance leads to exosomes-mediated retinal vascular SIPS and strategies aimed at halting this process could have therapeutic value to prevent/combat diabetic retinal microangiopathy and, potentially, DR. We have designed studies to validate our working hypothesis, but also aimed at extending the present knowledge of the molecular and cellular mechanisms promoting microangiopathy in the diabetic retina. Our aims are: Aim1 To investigate the contribution of HDAC6 to retinal vascular senescence, diabetic microangiopathy and DR. Aim2 To investigate the effects of enhancing/rescuing SIRT1 on vascular senescence, diabetic retinal microangiopathy, and DR. The results of our proposed studies will unveil an important pathogenic hub by confirming the existence of a negative feedback between HDAC6 and SIRT-1 and by revealing specific acetylome and exosomes signatures, thus enabling the identification of new diagnostic and therapeutic tools for retinal microangiopathy and DR.